Comparative assessment of antitumor effects and autophagy induction as a resistance mechanism by cytotoxics and EZH2 inhibition in INI1-negative epithelioid sarcoma patient-derived xenograft

Silvia Stacchiotti, Valentina Zuco, Monica Tortoreto, Denis Cominetti, Anna Maria Frezza, Stefano Percio, Valentina Indio, Marta Barisella, Valentina Monti, Silvia Brich, Annalisa Astolfi, Chiara Colombo, Sandro Pasquali, Marco Folini, Mrinal M. Gounder, Maria A. Pantaleo, Paola Collini, Angelo Paolo Dei Tos, Paolo Giovanni Casali, Alessandro GronchiNadia Zaffaroni

Research output: Contribution to journalArticle

Abstract

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

Original languageEnglish
Article number1015
JournalCancers
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 2019

Fingerprint

gemcitabine
Autophagy
Heterografts
Sarcoma
Ifosfamide
Anthracyclines
Residual Neoplasm
Tumor Burden
Doxorubicin
Neoplasms
Clinical Trials
Cell Line
Survival
Therapeutics

Keywords

  • Autophagy
  • Epithelioid sarcoma
  • EZH2
  • HMGA2
  • PDX

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{fb3924c56771480da84a8c77bb0d44fa,
title = "Comparative assessment of antitumor effects and autophagy induction as a resistance mechanism by cytotoxics and EZH2 inhibition in INI1-negative epithelioid sarcoma patient-derived xenograft",
abstract = "Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90{\%}) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.",
keywords = "Autophagy, Epithelioid sarcoma, EZH2, HMGA2, PDX",
author = "Silvia Stacchiotti and Valentina Zuco and Monica Tortoreto and Denis Cominetti and Frezza, {Anna Maria} and Stefano Percio and Valentina Indio and Marta Barisella and Valentina Monti and Silvia Brich and Annalisa Astolfi and Chiara Colombo and Sandro Pasquali and Marco Folini and Gounder, {Mrinal M.} and Pantaleo, {Maria A.} and Paola Collini and Tos, {Angelo Paolo Dei} and Casali, {Paolo Giovanni} and Alessandro Gronchi and Nadia Zaffaroni",
year = "2019",
month = "7",
doi = "10.3390/cancers11071015",
language = "English",
volume = "11",
journal = "Cancers",
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T1 - Comparative assessment of antitumor effects and autophagy induction as a resistance mechanism by cytotoxics and EZH2 inhibition in INI1-negative epithelioid sarcoma patient-derived xenograft

AU - Stacchiotti, Silvia

AU - Zuco, Valentina

AU - Tortoreto, Monica

AU - Cominetti, Denis

AU - Frezza, Anna Maria

AU - Percio, Stefano

AU - Indio, Valentina

AU - Barisella, Marta

AU - Monti, Valentina

AU - Brich, Silvia

AU - Astolfi, Annalisa

AU - Colombo, Chiara

AU - Pasquali, Sandro

AU - Folini, Marco

AU - Gounder, Mrinal M.

AU - Pantaleo, Maria A.

AU - Collini, Paola

AU - Tos, Angelo Paolo Dei

AU - Casali, Paolo Giovanni

AU - Gronchi, Alessandro

AU - Zaffaroni, Nadia

PY - 2019/7

Y1 - 2019/7

N2 - Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

AB - Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

KW - Autophagy

KW - Epithelioid sarcoma

KW - EZH2

KW - HMGA2

KW - PDX

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U2 - 10.3390/cancers11071015

DO - 10.3390/cancers11071015

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JO - Cancers

JF - Cancers

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